Painful Temporomandibular Disorder: Decade of Discovery from OPPERA Studies

Abstract

In 2006, the OPPERA project (Orofacial Pain: Prospective Evaluation and Risk Assessment) set out to identify risk factors for development of painful temporomandibular disorder (TMD). A decade later, this review summarizes its key findings. At 4 US study sites, OPPERA recruited and examined 3,258 community-based TMD-free adults assessing genetic and phenotypic measures of biological, psychosocial, clinical, and health status characteristics. During follow-up, 4% of participants per annum developed clinically verified TMD, although that was a "symptom iceberg" when compared with the 19% annual rate of facial pain symptoms. The most influential predictors of clinical TMD were simple checklists of comorbid health conditions and nonpainful orofacial symptoms. Self-reports of jaw parafunction were markedly stronger predictors than corresponding examiner assessments. The strongest psychosocial predictor was frequency of somatic symptoms, although not somatic reactivity. Pressure pain thresholds measured at cranial sites only weakly predicted incident TMD yet were strongly associated with chronic TMD, cross-sectionally, in OPPERA's separate case-control study. The puzzle was resolved in OPPERA's nested case-control study where repeated measures of pressure pain thresholds revealed fluctuation that coincided with TMD's onset, persistence, and recovery but did not predict its incidence. The nested case-control study likewise furnished novel evidence that deteriorating sleep quality predicted TMD incidence. Three hundred genes were investigated, implicating 6 single-nucleotide polymorphisms (SNPs) as risk factors for chronic TMD, while another 6 SNPs were associated with intermediate phenotypes for TMD. One study identified a serotonergic pathway in which multiple SNPs influenced risk of chronic TMD. Two other studies investigating gene-environment interactions found that effects of stress on pain were modified by variation in the gene encoding catechol O-methyltransferase. Lessons learned from OPPERA have verified some implicated risk factors for TMD and refuted others, redirecting our thinking. Now it is time to apply those lessons to studies investigating treatment and prevention of TMD.

Keywords: chronic pain; cohort studies; gene-environment interaction; human COMT protein; pain threshold; psychological stress.

Conflict of interest statement

The authors declare no other potential conflicts of interest with respect to the authorship and/or publication of this article.

© International & American Associations for Dental Research 2016.

Figures

Figure 1.

Pressure pain thresholds fluctuate with, but do not predict, onset and persistence of painful temporomandibular disorder (TMD). Reprinted from Slade et al. (2014). Adjusted mean pressure pain thresholds pooled from 5 anatomic locations measured at 3 visits in each of 3 study groups: OPPERA nested case-control study of TMD incidence. After enrollment (visit 1), the first follow-up (visit 2) occurred when TMD first developed or the matched control was selected, varying from 0.2 to 4.5 y after visit 1. The second follow-up (visit 3) occurred approximately 8 mo after visit 2 (range = 6 to 15 mo). Data are from 72 persistent TMD cases who developed first-onset TMD at visit 2 that persisted at visit 3 (●), 75 transient TMD cases who developed first-onset TMD at visit 2 that remitted at visit 3 (X), and 126 TMD-free controls (○). Symbols represent P values testing the null hypothesis that the adjusted mean threshold at one visit is equal to the adjusted mean threshold at the preceding visit in the same study group: ‡P < 0.01; †0.01 < P < 0.05. *Reference values for chronic TMD are from Greenspan et al. (2011). OPPERA, Orofacial Pain: Prospective Evaluation and Risk Assessment.

Figure 2.

Cellular pathways associated with localized temporomandibular disorder. From Slade, Smith, et al. (2013). Genes shown in blue are significantly associated with case status (P < 0.05). HTR2A, 5-hydroxytryptamine receptor 2A (OMIM 182135); HTR2C, 5-hydroxytryptamine receptor 2C (OMIM 312861); MAPK1, mitogen-activated protein kinase 1 (OMIM 176948); MAP2K1, mitogen-activated protein kinase 1 (OMIM 176872).

Figure 3.

Psychological stress increases in participants with low-activity catechol O-methyltransferase (COMT) diplotypes who develop first-onset temporomandibular disorder (TMD) but not in other groups. From Slade et al. (2015). Adjusted mean Perceived Stress Scale (PSS) scores at 4 time points for incident cases of first-onset TMD (●) and TMD-free controls (○), stratified according to diplotypes of the gene encoding COMT: (A) incident cases (n = 96) and TMD-free controls (n = 90) with low-activity COMT diplotypes (HPS-APS, HPS-HPS, APS-APS, or HPS-LPS); (B) incident cases (n = 84) and TMD-free controls (n = 63) with high-activity COMT diplotypes (LPS-LPS or LPS-APS). The 4 periods were as follows: the day of the baseline visit, when all participants were TMD free; intermediate follow-up, the quarterly periods after enrollment but before the penultimate quarter; the penultimate follow-up, the quarterly period preceding the final quarter; and the final follow-up, the quarterly period that coincided with the clinical visit at which incident TMD was determined. Error bars represent ±1 standard error (se) of the adjusted mean. Data points denoted by a star (★) represent PSS scores that differ significantly (P < 0.05) from baseline for participants with the same case classification within the same stratum of COMT diplotype. low (LPS), average (APS), and high pain sensitive (HPS).

Figure 4.

Sleep quality worsens prior to onset of temporomandibular disorder (TMD) in incident cases while remaining unchanged for matched controls. Reproduced from Sanders et al. (2016). Sleep quality was rated on a scale of 0 to 10 (0 = worst sleep, 10 = best sleep) in questionnaires completed once every quarter during follow-up of first-onset TMD cases (n = 220) and controls (n = 193) in the OPPERA nested case-control study. The 4 periods on the horizontal axis refer to the following: the first quarter (i.e., 3 mo) after enrollment; the intermediate quarters, between the first and penultimate quarters; the penultimate quarter, 3 mo before the final quarter; and the final quarter, the 3-mo interval prior to the follow-up visit at which presence or absence of TMD was determined. Error bars represent ±1 standard error (se) of the adjusted mean. Estimates are adjusted for study site, sex, age in years, and race/ethnicity. Asterisk (*) signifies a statistically significant difference (P < 0.05) as compared with the first quarter in the same study group. OPPERA, Orofacial Pain: Prospective Evaluation and Risk Assessment.